Hypercholesterolemia is known to be one of the prime risk factors for ischemic cardiovascular disease, such as arteriosclerosis. Bile acid sequestrants have been used to treat this condition; they seem to be moderately effective but they must be consumed in large quantities, i.e. several grams at a time and they are not very palatable.
MEVACOR.RTM. (lovastatin), now commercially available, is one of a group of very active antihypercholesterolemic agents that function by limiting cholesterol biosynthesis by inhibiting the enzyme, HMG-CoA reductase. In addition to the natural fermentation products, mevastatin and lovastatin, there are a variety of semi-synthetic and totally synthetic analogs thereof.
The naturally occurring compounds and their semi-synthetic analogs have the following general structural formulae: ##STR1## wherein: R.sup.3 is hydrogen, C.sub.1-5 alkyl or C.sub.1-5 alkyl substituted with a member of the group consisting of phenyl, dimethylamino, or acetylamino; and
R* is ##STR2## wherein Q is ##STR3## R.sup.5 is H or OH; M is ##STR4## R.sup.6 is hydrogen or hydroxy; R.sup.2 is hydrogen or methyl; and a, b, c, and d represent single bonds, one of a, b, c or d represents a double bond, or both a and c or both b and d represent double bonds provided that when a is a double bond, Q is ##STR5## and when d is a double bond, M is ##STR6## PA1 R.sub.1 and R.sub.2 independently are hydrogen, C.sub.1-5 alkyl, or R.sub.1 and R.sub.2 together with the carbon atom to which they are attached form a carbocyclic ring of 3 to 8 carbon atoms; PA1 R.sub.3 and R.sub.4 are independently hydrogen, C.sub.1-3 alkyl, C.sub.3-7 cycloalkyl, C.sub.1-3 alkylthio, phenyl, phenylthio or substituted phenyl in which the substituents are V and W and when n is 2 to 3, each of the R.sub.3 s and R.sub.4 s are independently hydrogen, C.sub.1-3 alkyl, C.sub.3-7 cycloalkyl or only one of the R.sub.3 s or R.sub.4 s on the chain of carbons is phenyl or substituted phenyl; PA1 R.sub.5 is hydrogen, tosylate, OT, C.sub.1-5 alkyl or C.sub.1-5 alkyl substituted with tosylate or OT, C.sub.3-7 cycloalkyl or C.sub.3-7 cycloalkyl substituted with C.sub.1-3 alkyl, tosylate or OT; C.sub.2-5 alkenyl, phenyl or substituted phenyl in which the substituents are V and W, or R.sub.5 is a group selected from: PA1 V and W independently are hydrogen, halogen, hydroxy, trifluoromethyl, C.sub.1-3 alkyl, C.sub.1-3 alkyloxy and TO-C.sub.1-3 alkyl; with a hydroxyl protecting compound such as tert-butyldimethylsilyl chloride, tert-butyldiphenylsilyl chloride, trimethylsilyl chloride, triethylsilyl chloride, triisopropylsilyl chloride or dihydropyran to yield a compound (2) wherein ##STR18## T is a hydroxyl protecting group such as tert-butyldimethylsilyl, tert-butyldiphenylsilyl, trimethylsilyl, triethylsilyl, triisopropylsilyl or tetrahydropyranyl; PA1 (i) contacting intermediate (9) with an acid in a polar solvent to yield compound (I): ##STR26## wherein R.sub.5 ' is identical to R.sub.5 except that any OT protecting group is hydrolyzed to OH. PA1 R.sub.1 is methyl; PA1 R.sub.2 is hydrogen or methyl; PA1 R.sub.3 and R.sub.4 are independently hydrogen or C.sub.1-3 alkyl. PA1 R.sub.5 is hydrogen, tosylate, OT, C.sub.1-5 alkyl, phenyl or substituted phenyl in which the substituents are V and W; PA1 T is tert-butyldimethylsilyl. PA1 (1) n is 0, R.sub.2 is methyl, R.sub.5 is ethyl; PA1 (2) n is 0, R.sub.2 is hydrogen, R.sub.5 is ethyl. PA1 R.sub.1 is methyl; PA1 R.sub.2 is hydrogen or methyl; PA1 R.sub.3 and R.sub.4 are independently hydrogen or C.sub.1-3 alkyl. PA1 R.sub.5 is hydrogen, tosylate, OT, C.sub.1-5 alkyl, phenyl or substituted phenyl in which the substituents are V and W; PA1 T is tert-butyldimethylsilyl. PA1 (1) n is 0, R.sub.2 is methyl, R.sub.5 is ethyl; PA1 (2) n is 0, R.sub.2 is hydrogen, R.sub.5 is ethyl.
U.S. Pat. No. 4,517,373 discloses semisynthetic hydroxy containing compounds represented by the above general formula wherein R* is ##STR7##
U.S. Pat. No. 4,537,859 and U.S. Pat. No. 4,448,979 also disclose semi-synthetic hydroxy-containing compounds represented by the above general formula wherein R* is ##STR8##
These compounds are prepared by the action of certain microorganisms on the corresponding non-hydroxylated substrates. One such organism described in U.S. Pat. No. 4,537,859 is of the genus Nocardia.
U.S. Pat. No. 4,376,863 discloses a fermentation product, isolated after cultivation of a microorganism belonging to the genus Aspergillus, which has a hydroxy containing butyryloxy side chain and is represented by the above general formula wherein R* is ##STR9##
Japanese unexamined patent application J59-122,483-A discloses a semi-synthetic hydroxy-containing compound represented by the above general formula wherein R* is ##STR10##
Copending U.S. patent application Ser. No. 048,136 filed May 15, 1987 discloses 6-substituted compounds of the above general formula wherein R* is ##STR11## wherein R is CH.sub.2 OH, ##STR12## and R.sup.1, R.sup.4, R.sup.7, R.sup.8 and R.sup.9 are broadly defined organic moieties.
The compounds of the above-mentioned U.S. patent application, Ser. No. 048,136 wherein a and c are double bonds were prepared by a microbiological conversion of lovastatin or an analog thereof with a 6-methyl substituent. Compounds where one of a, b or c represent a double bond or a, b, c all represent single bonds were prepared by a synthetic sequence from the 8-hydroxy-6-methyl derivative.
Copending U.S. patent application Ser. No. 131695 filed Dec. 11 1987 discloses a intermediates and processes for preparing 6-desmethyl-6-carboxy derivatives of lovastatin and 8-acyl analogs wherein the 6-carboxy moiety has the alpha stereochemical configuration.
Copending U.S. patent applications, Ser. No. 161530 and 16/579 filed 2-29-88, disclose intermediates and processes for preparing 6-desmethyl-6-hydroxymethyl derivatives of lovastatin and 8-acyl analogs, wherein the 6-hydroxymethyl moiety has the alpha stereochemical configuration.
The literature discloses a reaction known as the Barton Reaction by which a hydrogen on the .gamma. carbon to a COH group can be abstracted to afford a carbon radical which can be oxidized. (See Hesse Adv. Free-Radical Chem. 3, 83-137 (1969); Barton, Pure Appl. Chem. 16, 1-15 (1968); Arthar, Adv. Photochem. 2, 263-304 (1964).